CZ297897B6 - Acylation process - Google Patents

Abstract

In the present invention, there is described acylation process of indoles, specifically the preparation of 3-acylated indoles which may be further treated to provide indoles having an alternative substituent at the 3-position.

Description

(57)

Described is a process for the indole acylation, specifically a process for preparing 3-acylated indoles, which can be further processed to indoles having an alternative substituent at the 3-position.

WHAT

O) what r * σ>

CM N

O

Method of acylation

Technical field

The invention relates to a process for the acylation of indoles, in particular to the preparation of 3-acylated indoles which can be further processed to indoles having an alternative substituent at the 3-position.

BACKGROUND OF THE INVENTION

Until now, 3-acylation of indoles is typically carried out as described, for example, in International Patent Application PCT / US91 / 07194, i.e. by reacting an indole magnesium salt with an acid chloride:

wherein Z is halogen and R is, for example, substituted pyrrolidinyl, azetidinyl or piperidinyl.

The magnesium salt is prepared by reacting the corresponding indole with an alkyl or aryl magnesium halide, preferably ethylmagnesium bromide, in an inert solvent such as diethyl ether or tetrahydrofuran at a temperature between -30 and 65 ° C, preferably about 25 ° C.

The acid chloride is prepared by reacting the corresponding acid with, for example, oxalyl chloride or thionyl chloride, in an inert solvent, for example, methylene chloride, diethyl ether or tetrahydrofuran, at a temperature between -10 and 25 ° C. Acids having a heterocyclic moiety of the nitrogen-containing molecule or may be protected from N-substitution with acyl chloride using a suitable protecting group, for example, carboxybenzyl (CBZ).

The acid chloride solution is then slowly added to the stirred solution of the magnesium salt at a temperature between -30 and 50 ° C, preferably at a temperature of about 25 ° C to give the desired 3-acylated indole.

This process for the preparation of 3-acylated indoles requiring independent preparation of the starting materials is both time consuming and laborious and is not readily accomplished on a commercial scale.

SUMMARY OF THE INVENTION

Therefore, a new process for the preparation of 3-acylated indoles has been developed which eliminates the need for independent preparation of the above starting materials. The present invention provides a process for the preparation of 3-acylated indoles which are obtained in good yield by adding acid chloride solutions (N-protected if necessary) and an alkyl or aryl magnesium halide separately and simultaneously to the indole solution at "synchronized" molar addition rates.

Thus, it is an object of the present invention to provide a fast and cost effective process for the preparation of 3-acylated indoles which avoids the insufficiently convergent prior art synthesis, in particular the need to prepare and isolate the magnesium salt of the indole.

- 1 GB 297897 B6

Another economical measure of the process of the present invention is that it requires only one molar equivalent of the expensive indole starting material. This contrasts with the two equivalents required in the prior art process and effectively doubles the yield of the starting indole acylated substance.

According to the present invention, there is provided a process for preparing 3-acylated indoles by preparing an acid chloride as described above, and then adding (1) an acid chloride and (2) an alkyl or aryl-magnesium halide solution separately and simultaneously to the a mixed indole solution such that (a) the two streams of the incoming reactants do not come into direct contact with each other, i.e., they are added at a distance to prevent them from interacting with the indole and (b) the two reactants are added at "synchronized" amounts of molar addition.

In particular, the invention provides a process for the preparation of a compound of formula I, COR wherein R is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, or aryl optionally substituted with one or more hydroxy groups , (C1-C4) -alkyl, (C1-C4) -alkoxy, fluoro, (C1-C4) fluoroalkyl and (C1-C4) fluoroalkoxy and X is hydrogen or one or more substituents independently selected from: cyano, halogen, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl and aryl optionally substituted with one or more cyano, halogen, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, fluoroalkyl C 1 -C 4 and C 1 -C 4 fluoroalkoxy, which is added separately and simultaneously to a stirred solution of the indole II

wherein X is as defined above, (1) an acid chloride-containing solution of the formula RCOC1, wherein R is as defined above, and (2) a solution containing an alkyl or aryl-magnesium halide in such a way that (a) solutions (1) and ( 2) are added separately separately to prevent their mutual reaction; and (b) solution (1) and (2) are added in equivalent amounts of molar addition.

According to a particularly preferred embodiment of the invention, the indole of the formula II is indole alone or 5-halogenated indole and the magnesium halide is an alkyl or aryl-magnesium bromide, preferably ethyl magnesium bromide.

-2GB 297897 B6

The present invention is further illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of 3- (N-CBZ-2-pyrrolidinylcarboxy) -5-bromoindole

In a freshly dried flask equipped with the above stirrer and kept under a nitrogen atmosphere was charged 5-bromoindole (3.85 kg, 19.6 mol) followed by methylene chloride (12.3 L). The resulting mixture was stirred at room temperature until a homogeneous solution was obtained and then cooled to 10-12 ° C. Then, solutions of CBZ-prolinoyl chloride in methylene chloride (20 mol, 1.02 eq.) And 1 M ethylmagnesium bromide in MTBE (37.7 kg, 39.2 mol, 2 eq.) Are simultaneously added over 2 to 3 hours on opposite sides of the vessel. while maintaining the temperature at 10-15 ° C. The addition must be carried out so that the two streams do not mix and that the molar addition rate of each reactant is continuously synchronized.

The resulting suspension was added over 30 minutes to a vigorously stirred mixture of concentrated HCl (3 L), demineralized water (28 L) and THF (29 L), maintaining the temperature below 25 ° C. The resulting biphasic mixture was stirred for 30 minutes, allowed to settle for 20 minutes, then the phases were separated while maintaining the upper organic layer. The organic layer was washed for 20 minutes with saturated aqueous NaHCO ₃ (28 L) at 20-25 ° C, allowed to settle for 20 minutes, and then the phases were separated, maintaining the top organic layer. The solvents were then removed under reduced pressure, maintaining the temperature below 50 ° C, during which crystallization was observed during the last stage. Ethyl acetate (15.5 L) and hexane (15.5 L) were added to the resulting suspension, and the resulting mixture was cooled to 0 ° C and granulated at this temperature for 1 hour. The product was then isolated by filtration, washed with 1: 1 hexane: ethyl acetate (101) and dried overnight under reduced pressure at 35 ° C to give 6.85 kg (82%) of (R) -3- (N-carboxybenzoyl-2-pyrrolidinylcarboxy) -5-bromo-1H-indole as fine white crystals.

Calculated: C = 59.03%, H = 4.48%, N = 6.56%

Found: C = 59.01%, H = 4.50%, N = 6.58%.

Example 2

Preparation of 3- (N-CBZ-2-pyrrolidinylcarboxy) indole

To a solution of 25 mmol of indole in methylene chloride (25 mL) was added simultaneously a solution of CBZ-prolinoyl chloride (25 mmol) in 25 mL of MTBE and 50 mL of a 1 M solution of ethylmagnesium bromide in MTbE over 1 h. The two streams are added on opposite sides of the vessel with efficient agitation and the temperature is maintained at 10-15 ° C. After the addition was complete, the reaction was quenched by addition to 1.0 M aqueous HCl (50 mL). After stirring, settling and phase separation, the organic phase was washed with brine (50 ml) and then reduced to 75% to begin crystallization of the product. The product was filtered off, washed with ethyl acetate (~ 10 ml) and dried under reduced pressure at 45 ° C. Yield 81%.

Example 3

Preparation of 3-benzoyl-5-bromoindole

3-Benzoyl-5-bromoindole was obtained in 94% yield using the procedure described in Example 2.

Example 4

Preparation of 3-benzoylindole

3-Benzoylindole was obtained in 91% yield using the procedure described in Example 2.

It will be apparent to those skilled in the art that the 3-acylated indoles obtained by the process of the invention can be further processed to indoles having the 3-position alternative substituent.

Thus, in a specific embodiment of the present invention, when R is N-CBZ-2-pyrrolidinylcarboxy) -5-bromoindole of formula I is a compound of formula

which can then be reduced, for example with lithium aluminum hydride in tetrahydrofuran, to give 3- (N-methyl-2 (R) -pyrrolidinylmethyl) -5-bromoindole of formula III

which can then be converted using the appropriate Heck reaction to 3- (N-methyl-2 (R) -pyrrolidinylmethyl) -5- (2-phenylsulfonylethenyl) -1H-indole of formula IV

which in turn can be catalytically hydrogenated to give 3- (N-methyl-2 (R) -pyrrolidinylmethyl) -5- (2-phenylsulfonylethyl) -1H-indole of formula V

The compound is known as a 5-HT 1 agonist used in the treatment of migraine.

Claims (11)

PATENT CLAIMS A process for the preparation of a 3-acylated indole of the formula I, COR (I) wherein R is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, or aryl, optionally substituted with one or more hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, fluoro, C 1 -C 4 fluoroalkyl and C 1 -C 4 fluoroalkoxy and X is hydrogen or one or a plurality of substituents independently selected from the group consisting of cyano, halogen, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl and aryl optionally substituted with one or more cyano, halogen atoms, nitro groups, alkyl groups of 1 to 4 carbon atoms, alkoxy groups of 1 to 4 carbon atoms, fluoroalkyl groups (C1-C4) -fluoroalkoxy having 1 to 4 carbon atoms, characterized in that a mixed solution of an indole of formula (II) wherein X is as defined above, is added separately and simultaneously, (1) a solution containing an acid chloride of formula RCOC1; wherein R is as defined above, and (2) a solution containing an alkyl or aryl-magnesium halide in such a way that (a) solutions (1) and (2) are added separately enough to prevent their reaction with each other, and (b) solutions (1) and (2) are added in equivalent amounts of molar addition. -5 CZ 297897 B6 The process according to claim 1, wherein the indole of formula II is indole alone or 5-halogenated indole. The process according to claim 1 or 2, wherein the magnesium halide is an alkyl or aryl-magnesium bromide. A process according to any one of claims 1 to 3, wherein the magnesium halide is ethylmagnesium bromide. Process according to any one of claims 1 to 4, characterized in that the compound of formula I obtained is a compound of formula A process according to claim 5, characterized in that the obtained compound of formula I is subsequently reduced to give a compound of formula III The method of claim 6, wherein the reduction is carried out using lithium aluminum hydride in tetrahydrofuran. The process according to claims 6 and 7, characterized in that the compound of formula III thus obtained is subsequently converted to a compound of formula IV The process of claim 8, wherein the conversion is carried out using a suitable Heck reaction. -6GB 297897 B6 Process according to claims 8 and 9, characterized in that the compound of formula IV thus obtained is subsequently converted into a compound of formula V Process according to claim 10, characterized in that the conversion is carried out by catalytic hydrogenation.